tbuckley/cabot-search huggingface dataset:
Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans
Authors: Shiqi Zhong, Raphael Chèvre, David Castaño Mayan, Maria Corlianò, Blake J. Cochran, Kai Ping Sem, Theo H. van Dijk, Jianhe Peng, Liang Juin Tan, Siddesh V. Hartimath, Boominathan Ramasamy, Peter Cheng, Albert K. Groen, Folkert Kuipers, Julian L. Goggi, Chester Drum, Rob M. van Dam, Ru San Tan, Kerry-Anne Rye, Michael R. Hayden, Ching-Yu Cheng, Shaji Chacko, Jason Flannick, Xueling Sim, Hong Chang Tan, Roshni R. Singaraja
Journal: Journal of Clinical Investigation (2022)

BACKGROUNDCytochrome P450 family 8 subfamily B member 1 (CYP8B1) generates 12α-hydroxylated bile acids (BAs) that are associated with insulin resistance in humans.METHODSTo determine whether reduced CYP8B1 activity improves insulin sensitivity, we sequenced CYP8B1 in individuals without diabetes and identified carriers of complete loss-of-function (CLOF) mutations utilizing functional assays.RESULTSMutation carriers had lower plasma 12α-hydroxylated/non-12α-hydroxylated BA and cholic acid (CA)/chenodeoxycholic acid (CDCA) ratios compared with age-, sex-, and BMI-matched controls. During insulin clamps, hepatic glucose production was suppressed to a similar magnitude by insulin, but glucose infusion rates to maintain euglycemia were higher in mutation carriers, indicating increased peripheral insulin sensitivity. Consistently, a polymorphic CLOF CYP8B1 mutation associated with lower fasting insulin in the AMP-T2D-GENES study. Exposure of primary human muscle cells to mutation-carrier CA/CDCA ratios demonstrated increased FOXO1 activity, and upregulation of both insulin signaling and glucose uptake, which were mediated by increased CDCA. Inhibition of FOXO1 attenuated the CDCA-mediated increase in muscle insulin signaling and glucose uptake. We found that reduced CYP8B1 activity associates with increased insulin sensitivity in humans.CONCLUSIONOur findings suggest that increased circulatory CDCA due to reduced CYP8B1 activity increases skeletal muscle insulin sensitivity, contributing to increased whole-body insulin sensitization.FUNDINGBiomedical Research Council/National Medical Research Council of Singapore.
CD8+ T cell memory is sustained in mice by hepatic stellate cells
Authors: Yi‐Ting Chen, Yu‐Chia Su, Yee‐Ern Or, Chin‐Fu Cheng, John T. Kung
Journal: Hepatology (2022)

Background and Aims: Long‐lasting immunological memory is the ultimate goal of vaccination. Homeostatic maintenance of memory CD8 + cytotoxic T cells (MemCD8TCs) is thought to be mediated by IL‐15/IL‐15R heterodimer (15HD)‐expressing myeloid cells. Nonmyeloid hepatic stellate cells (HSCs) also express 15HD, but their role in maintaining MemCD8TC homeostasis is unknown. Approach and Results: We engineered a genetically engineered mouse in which IL‐15R complementary DNA (cDNA) had been inserted in‐frame with lecithin‐retinol acyltransferase gene and bred onto an IL‐15R‐KO (15R‐KO) genetic background (L15R) that expressed IL‐15R in HSCs at normal levels, but not in other liver cells. Outside of the liver of L15R mice, IL‐15R expression was found in a number of organs, but not in dendritic cells and macrophages. The low IL‐15R expression in the bone marrow (BM) of L15R mice was eliminated by the reconstitution of lethally‐irradiated L15R mice with 15R‐KO BM to generate L15RC mice. Because MemCD8TC maintenance is mediated by 15HD, not empty IL‐15R, 15HD content in L15R mice was determined and found for liver, lung, kidney, and heart. L15R and L15RC mice developed and maintained long‐lasting, systemic antigen‐specific MemCD8TCs that were efficacious against tumor growth and Listeria monocytogenes infection in an antigen‐specific manner. Among the four organs with 15HD content, liver‐associated MemCD8TCs were different from those found in the lung, kidney, and heart in two ways: (1) they were quantitatively the most numerous, and (2) they appeared uniquely in the form of clusters in a specialized structure, sinusoidal niches of the liver. Conclusions: The liver, the largest organ of the body, is endowed with the capability of effectuating long‐lasting functional cytotoxic T cell memory.
The maternal prenatal and offspring <scp>early‐life</scp> gut microbiome of childhood asthma phenotypes
Authors: Kathleen A. Lee‐Sarwar, Yih‐Chieh Chen, Yuan Yao Chen, Anita L. Kozyrskyj, Piush J. Mandhane, Stuart E. Turvey, Padmaja Subbarao, Hans Bisgaard, Jakob Stokholm, Bo Chawes, Søren J. Sørensen, Rachel S. Kelly, Jessica Lasky‐Su, Robert S. Zeiger, George T. O'Connor, Megan T. Sandel, Leonard B. Bacharier, Avraham Beigelman, Vincent J. Carey, Benjamin J. Harshfield, Nancy Laranjo, Diane R. Gold, Scott T. Weiss, Augusto A. Litonjua
Journal: Allergy (2022)

The infant fecal microbiome is known to impact subsequent asthma risk, but the environmental exposures impacting this association, the role of the maternal microbiome, and how the microbiome impacts different childhood asthma phenotypes are unknown.
Use of 15-Valent Pneumococcal Conjugate Vaccine Among U.S. Children: Updated Recommendations of the Advisory Committee on Immunization Practices — United States, 2022
Authors: Miwako Kobayashi, Jennifer L. Farrar, Ryan Gierke, Andrew J. Leidner, Doug Campos-Outcalt, Rebecca L. Morgan, Sarah S. Long, Katherine A. Poehling, Adam L. Cohen, Katherine A. Poehling, Sarah S. Long, Jeffrey Kelman, Lucia Lee, Tina Mongeau, Thomas Weiser, Uzo Chukwuma, Kristina Lu, Mamodikoe Makhene, Lynn Fisher, Mark Sawyer, Jason Goldman, David Nace, Emily Messerli, Elissa Abrams, Aleksandra Wierzbowski, Carol Baker, James McAuley, William Schaffner, Virginia Cane, Doug Campos-Outcalt, Monica M. Farley, Keith Klugman, Rebecca L. Morgan, Arthur Reingold, Lorry Rubin, Cynthia Whitney, Richard K. Zimmerman, Emma Accorsi, Alison Albert, Shriya Bhatnagar, Lana Childs, Marc Fischer, Rachel Gorwitz, Angela Jiles, Heidi Moline, Pedro Moro, Chukwuebuka Nsofor, Namrata Prasad, Heather Walker, Jacquline Risalvato, Sarah Schillie
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

The 13-valent pneumococcal conjugate vaccine (PCV13 [Prevnar 13, Wyeth Pharmaceuticals, Inc, a subsidiary of Pfizer, Inc]) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23 [Merck Sharp & Dohme LLC]) have been recommended for U.S. children, and the recommendations vary by age group and risk group (1,2). In 2021, 15-valent pneumococcal conjugate vaccine (PCV15 [Vaxneuvance, Merck Sharp & Dohme LLC]) was licensed for use in adults aged ≥18 years (3). On June 17, 2022, the Food and Drug Administration (FDA) approved an expanded usage for PCV15 to include persons aged 6 weeks-17 years, based on studies that compared antibody responses to PCV15 with those to PCV13 (4). PCV15 contains serotypes 22F and 33F (in addition to the PCV13 serotypes) conjugated to CRM197 (genetically detoxified diphtheria toxin). On June 22, 2022, CDC's Advisory Committee on Immunization Practices (ACIP) recommended use of PCV15 as an option for pneumococcal conjugate vaccination of persons aged <19 years according to currently recommended PCV13 dosing and schedules (1,2). ACIP employed the Evidence to Recommendation (EtR) Framework,* using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE)† approach to guide its deliberations regarding use of these vaccines. Risk-based recommendations on use of PPSV23 for persons aged 2-18 years with certain underlying medical conditions§ that increase the risk for pneumococcal disease have not changed.
Comparison of immunogenicity and clinical effectiveness between BNT162b2 and ChAdOx1 SARS-CoV-2 vaccines in people with end-stage kidney disease receiving haemodialysis: A prospective, observational cohort study
Authors: Paul Martin, Sarah Gleeson, Candice L. Clarke, Tina Thomson, Helena Edwards, Katrina Spensley, Paige Mortimer, Stacey McIntyre, Alison Cox, Graham Pickard, Liz Lightstone, David Thomas, Stephen P. McAdoo, Peter Kelleher, Maria Prendecki, Michelle Willicombe
Journal: The Lancet Regional Health - Europe (2022)

People with end-stage kidney disease, including people on haemodialysis, are susceptible to greater COVID-19 related morbidity and mortality. This study compares the immunogenicity and clinical effectiveness of BNT162B2 versus ChAdOx1 in haemodialysis patients. In this observational cohort study, 1021 patients were followed-up from time of vaccination until December 2021. All patients underwent weekly RT-PCR screening. Patients were assessed for nucleocapsid(anti-NP) and spike(anti-S) antibodies at timepoints after second(V2) and third(V3) vaccinations. 191 patients were investigated for T-cell responses. Vaccine effectiveness (VE) for prevention of infection, hospitalisation and mortality was evaluated using the formula VE=(1-adjustedHR)x100. 45.7% (467/1021) had evidence of prior infection. There was no difference in the proportion of infection-naïve patients who seroconverted by vaccine type, but median anti-S antibody titres were higher post-BNT162b2 compared with ChAdOx1; 462(152-1171) and 78(20-213) BAU/ml respectively, p<0.001. Concomitant immunosuppressant use was a risk factor for non-response, OR 0.12[95% CI 0.05-0.25] p<0.001. Post-V3 (all BNT162b2), median anti-S antibody titres remained higher in those receiving BNT162b2 versus ChAdOx1 as primary doses; 2756(187-1246) and 1250(439-2635) BAU/ml respectively, p=0.003.Anti-S antibodies waned over time. Hierarchical levels of anti-S post-V2 predicted risk of infection; patients with no/low anti-S being at highest risk. VE for preventing infection, hospitalisation and death was 53% (95% CI 6-75), 77% (95% CI 30-92) and 93% (95% CI 59-99) respectively, with no difference seen by vaccine type. Serum anti-S concentrations predict risk of breakthrough infection. Anti-S responses vary dependent upon clinical features, infection history and vaccine type. Monitoring of serological responses may enable individualised approaches to vaccine boosters in at risk populations. National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London.
Naturally derived indole alkaloids targeting regulated cell death (RCD) for cancer therapy: from molecular mechanisms to potential therapeutic targets
Authors: Rui Qin, Feng-Ming You, Qian Zhao, Xin Xie, Cheng Peng, Gu Zhan, Bo Han
Journal: Journal of Hematology & Oncology (2022)

Abstract Regulated cell death (RCD) is a critical and active process that is controlled by specific signal transduction pathways and can be regulated by genetic signals or drug interventions. Meanwhile, RCD is closely related to the occurrence and therapy of multiple human cancers. Generally, RCD subroutines are the key signals of tumorigenesis, which are contributed to our better understanding of cancer pathogenesis and therapeutics. Indole alkaloids derived from natural sources are well defined for their outstanding biological and pharmacological properties, like vincristine, vinblastine, staurosporine, indirubin, and 3,3′-diindolylmethane, which are currently used in the clinic or under clinical assessment. Moreover, such compounds play a significant role in discovering novel anticancer agents. Thus, here we systemically summarized recent advances in indole alkaloids as anticancer agents by targeting different RCD subroutines, including the classical apoptosis and autophagic cell death signaling pathways as well as the crucial signaling pathways of other RCD subroutines, such as ferroptosis, mitotic catastrophe, necroptosis, and anoikis, in cancer. Moreover, we further discussed the cross talk between different RCD subroutines mediated by indole alkaloids and the combined strategies of multiple agents (e.g., 3,10-dibromofascaplysin combined with olaparib) to exhibit therapeutic potential against various cancers by regulating RCD subroutines. In short, the information provided in this review on the regulation of cell death by indole alkaloids against different targets is expected to be beneficial for the design of novel molecules with greater targeting and biological properties, thereby facilitating the development of new strategies for cancer therapy. Graphic abstract
Monthly Cost-Sharing Limits and Out-of-pocket Costs for Commercially Insured Patients in the US
Authors: Paul R. Shafer, Michal Horný, Stacie B. Dusetzina
Journal: JAMA Network Open (2022)

This cross-sectional study assesses how much monthly cost-sharing limits, as opposed to annual limits, could reduce out-of-pocket costs for commercially insured patients in the US.
Pushing the Envelope for Active Surveillance
Authors: Andrea L. Merrill, Priya H. Dedhia
Journal: JAMA Oncology (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Substance Use Among Senior Medical Students
Authors: DeWitt C. Baldwin
Journal: JAMA (1991)

Senior students at 23 regionally distributed medical schools received an anonymous questionnaire designed to examine current and prior use of tobacco, alcohol, and nine other drugs. The overall response rate was 67% (N = 2046). Substance use prevalence rates during the 30 days preceding the survey included alcohol, 87.5%; marijuana, 10.0%; cigarettes, 10.0%; cocaine, 2.8%; tranquilizers, 2.3%; opiates other than heroin, 1.1%; psychedelics other than LSD (lysergic acid diethylamide), 0.6%; amphetamines, 0.3%; barbiturates, 0.2%; LSD, 0.1%; and heroin, 0.0%. Compared with national, age-related comparison groups, senior medical students reported less use of all substances during the past 30 days and the past 12 months, except for alcohol, tranquilizers, and psychedelics other than LSD. Substantial new drug use after entry into medical school was reported only for tranquilizers. Seven students (0.2%) admitted to current dependence on a substance other than tobacco, four of these implicating marijuana. Thirty-three students (1.6%) believed that they currently needed help for substance abuse. Only 25.7% were aware of any policy on substance abuse at their own school. (<i>JAMA</i>. 1991;265:2074-2078)
JAAD Case Reports Article List
Authors: Angela Moore, Kara Hurley, Gabriella Santa, Shahzeb Hassan, Mohannad Safadi, Dirk Elston, Jane Scribner, Carbamazepine-Induced Reversible, Vitiligo Luai, M Assaedi, Hussein Alshamrani, Renad Abbas, Fadi Alghamdi, Minorvi Amin, Christopher Liao, Roger Simpson, Kory Schrom, Sonal Shah, Bethany Rohr, Eijiro Akasaka, Hajime Nakano, Daisuke Sawamura, Noreen Mohsin, Scott Whitecar, Jacqueline Jones, John Childs, Isaac Brownell, Hyeok-Jin Kwon, Kyung-Deok Park, Jung-Ho Yoon, Rebecca Colwell, Daniel Bennett, Justin Endo, Rachel Sally, Randie Kim, Kristen Sicco, Avrom Caplan, Eleanor Pope, Kathryn Somers, Rodrigo Do, Carmo Silva, Dayvison Francis, Saraiva Freitas, Pedro Cabrera Pereira, Antonio Carlos Francesconi Do Valle, Maria Clara Gutierrez-Galhardo, Fernando Almeida-Silva, Felipe Mauricio, Soeiro Sampaio, Roger Rovira-Lo ´pez, Ramon Pujol, Sofia Antunes-Duarte, Ana Marcos-Pinto, Lars French, Heinz Kutzner, Luı ´s Soares-De-Almeida, Paul Wurtz, Robert Borucki, Corey Georgesen, Anon Paichitrojjana, Anand Paichitrojjana, Patricia Monnet, Martine Bagot, Jacqueline Rivet, Jennifer Roux, Antoine Petit, Jana Al-Hage, Yana Kost, Daiva Ba, Ahava Muskat, Roya Nazarian, Bijal Amin, Haiying Cheng, Beth Mclellan, Lina Chan, Harry Greenberg, Vinod Hanumanthu, Tarun Narang, Sunil Dogra
Journal: Journal of the American Academy of Dermatology (2022)
Table of Contents
Authors: Jette Hooper, Kimberly Shao, Hao Feng, Dirk Elston, Brett Sloan, Jonathan Kantor, Pedro Mendes-Bastos, Barry Ladizinski, Emma Guttman-Yassky, Ping Jiang, John Liu, Vimal Prajapati, Eric Simpson, Namita Vigna, Henrique Teixeira, Sebastien Barbarot, Debra Lee, Michelle Chang, Amar Desai, Shari Lipner, Bruce Strober, Linda Gold, Robert Bissonnette, April Armstrong, Leon Kircik, Stephen Tyring, Stephen Piscitelli, Philip Brown, David Rubenstein, Anna Tallman, Mark Lebwohl, David Xiong, Paola Barriera-Silvestrini, Thomas Knackstedt, Andrew Blauvelt, Richard Langley, Jean-Philippe Lacour, Darryl Toth, Vivian Laquer, Stefan Beissert, Andreas Wollenberg, Pedro Herranz, Andrew Pink, Ketty Peris, Stine Fangel, Le Gjerum, Joshua Corriveau, Hidehisa Saeki, Richard Warren, Kristian Reich, Alessandro Franciosi, James Ralph, Naoimh O'farrell, Colm Buckley, Christian Gulmann, Marina O'kane, Toma ´s, P Carroll, Noel Mcelvaney
Journal: Journal of the American Academy of Dermatology (2022)
Infectious diseases among travellers and migrants in Europe, EuroTravNet 2010
Authors: P Gautret, J P Cramer, V Field, E Caumes, M Jensenius, E Gkrania-Klotsas, P J de Vries, M P Grobusch, R Lopez-Velez, F Castelli, P Schlagenhauf, H Hervius Askling, F von Sonnenburg, D G Lalloo, L Loutan, C Rapp, F Basto, F Santos O’Connor, L Weld, P Parola, None for the EuroTravNet Network
Journal: Eurosurveillance (2012)

To investigate trends in travel-associated morbidity with particular emphasis on emerging infections with the potential for introduction into Europe, diagnoses of 7,408 returning travellers presenting to 16 EuroTravNet sites in 2010 were compared with 2008 and 2009. A significant increase in reported Plasmodium falciparum malaria (n=393 (6% of all travel-related morbidity) vs. n=267 (4%) and 296 (5%); p&lt;0.001), P. vivax malaria (n=53 (1%) vs. n=31 (0.5%) and 39 (1%); p=0.038) and dengue fever (n=327 (5%) vs. n=131 (2%) and 172 (2%); p&lt;0.001) was observed. Giardia lamblia was identified in 16% of patients with acute diarrhoea, with no significant annual variation. The proportion of acute diarrhoea due to Campylobacter increased from 7% in 2008 to 12% in 2010 (p=0.002). We recorded 121 patients with pulmonary tuberculosis in 2010, a three-fold increase in the proportionate morbidity from 2008 to 2010. In 2010, 60 (0.8%) cases of chronic Chagas disease, 151 (2%) cases of schistosomiasis and 112 (2%) cases of cutaneous larva migrans were reported. Illness patterns in sentinel travellers, captured by EuroTravnet, continue to highlight the potential role of travellers in the emergence of infectious diseases of public health concern in Europe and the relevance of offering medical travel advice and enforcing specific and adequate prophylaxis.*
Effectiveness and cost-effectiveness of oral nutritional supplements in frail older people who are malnourished or at risk of malnutrition: a systematic review and meta-analysis
Authors: Katie H Thomson, Stephen Rice, Oluwatomi Arisa, Eugenie Johnson, Louise Tanner, Christopher Marshall, Tumi Sotire, Catherine Richmond, Hannah O'Keefe, Wael Mohammed, Anne Raffle, Barbara Hanratty, Claire T McEvoy, Dawn Craig, Sheena E Ramsay
Journal: The Lancet Healthy Longevity (2022)
Combination treatment of mannose and GalNAc conjugated small interfering RNA protects against lethal Marburg virus infection
Authors: Xin Ye, Richard Holland, Mark Wood, Chris Pasetka, Lorne Palmer, Eleni Samaridou, Kevin McClintock, Viktoriya Borisevich, Thomas W. Geisbert, Robert W. Cross, James Heyes
Journal: Molecular Therapy (2022)

Marburg virus (MARV) infection results in severe viral hemorrhagic fever with mortalities up to 90%, and there is a pressing need for effective therapies. Here, we established a small interfering RNA (siRNA) conjugate platform that enabled successful subcutaneous delivery of siRNAs targeting the MARV nucleoprotein. We identified a hexavalent mannose ligand with high affinity to macrophages and dendritic cells, which are key cellular targets of MARV infection. This ligand enabled successful siRNA conjugate delivery to macrophages both in vitro and in vivo. The delivered hexa-mannose-siRNA conjugates rendered substantial target gene silencing in macrophages when supported by a mannose functionalized endosome release polymer. This hexa-mannose-siRNA conjugate was further evaluated alongside our hepatocyte-targeting GalNAc-siRNA conjugate, to expand targeting of infected liver cells. In MARV-Angola-infected guinea pigs, these platforms offered limited survival benefit when used as individual agents. However, in combination, they achieved up to 100% protection when dosed 24 h post infection. This novel approach, using two different ligands to simultaneously deliver siRNA to multiple cell types relevant to infection, provides a convenient subcutaneous route of administration for treating infection by these dangerous pathogens. The mannose conjugate platform has potential application to other diseases involving macrophages and dendritic cells.
Automated optimization of TMS coil placement for personalized functional network engagement
Authors: Charles J. Lynch, Immanuel G. Elbau, Tommy H. Ng, Danielle Wolk, Shasha Zhu, Aliza Ayaz, Jonathan D. Power, Benjamin Zebley, Faith M. Gunning, Conor Liston
Journal: Neuron (2022)

Transcranial magnetic stimulation (TMS) is used to treat multiple psychiatric and neurological conditions by manipulating activity in particular brain networks and circuits, but individual responses are highly variable. In clinical settings, TMS coil placement is typically based on either group average functional maps or scalp heuristics. Here, we found that this approach can inadvertently target different functional networks in depressed patients due to variability in their functional brain organization. More precise TMS targeting should be feasible by accounting for each patient's unique functional neuroanatomy. To this end, we developed a targeting approach, termed targeted functional network stimulation (TANS). The TANS approach improved stimulation specificity in silico in 8 highly sampled patients with depression and 6 healthy individuals and in vivo when targeting somatomotor functional networks representing the upper and lower limbs. Code for implementing TANS and an example dataset are provided as a resource.